Acetyl-CoA carboxylase inhibition alters tubulin acetylation and aggregation in thrombin-stimulated platelets

医学 血小板聚集 血小板 生物化学 凝血酶 微管蛋白 药理学 乙酰化 化学 微管 细胞生物学 内科学 基因 生物
作者
Marie Octave,Laurence Pirotton,Audrey Ginion,Valentine Robaux,Sophie Lepropre,Shakeel Kautbally,Victor Darley‐Usmar,Jérôme Ambroise,Bruno Guigas,Martin Giera,Marc Foretz,Luc Bertrand,Christophe Beauloye,Sandrine Horman
出处
期刊:Archives of Cardiovascular Diseases Supplements [Elsevier BV]
卷期号:13 (2): 182-183
标识
DOI:10.1016/j.acvdsp.2021.04.090
摘要

Acetyl-CoA carboxylase (ACC), the first enzyme regulating lipid synthesis, promotes thrombus formation by increasing platelet phospholipid content. Inhibition of its activity decreases lipogenesis and increases the content in acetyl-CoA which can serve as a substrate for protein acetylation. This posttranslational modification plays a key role in the regulation of platelet aggregation, via tubulin acetylation. To demonstrate that ACC inhibition may affect platelet functions via an alteration of lipid content and/or tubulin acetylation. Platelets were treated 2 hours with CP640.186, a pharmacological ACC inhibitor, prior to thrombin stimulation. Platelet functions were assessed by aggregometry and flow cytometry. Lipogenesis was measured via 14 C-acetate incorporation into lipids. Lipidomics analysis was carried out on the commercial Lipidyzer platform. Protein phosphorylation and acetylation were evaluated by western blot. Treatment with CP640.186 drastically decreased platelet lipogenesis. However, the quantitative lipidomics analyses showed that preincubation with the compound did not affect global platelet lipid content. Interestingly, this short-term ACC inhibition was sufficient to increase tubulin acetylation level, at basal state and after thrombin stimulation. It was associated with an impaired platelet aggregation, in response to low thrombin concentration, while granules secretion was not affected. Mechanistically, we highlighted a decrease in Rac1 activity, associated with a reduced phosphorylation of its downstream effector PAK2. Surprisingly, actin cytoskeleton was not impacted but we evidenced a significant decrease in ROS production, which could result from a decreased NOX2 activity. Pharmacological ACC inhibition decreases platelet aggregation upon thrombin stimulation. The mechanism depends on increased tubulin acetylation, with subsequent alteration of the Rac1/PAK2/NOX2 signaling pathway.
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